tbuckley/cabot-search huggingface dataset:
SURG-01. DIFFERENTIATION OF GLIOBLASTOMA AND MALIGNANT MENINGIOMA FROM NORMAL BRAIN BY TISSUE STIFFNESS UTILIZING MICROSURGICAL FORCEPS EQUIPPED WITH HAPTICS TECHNOLOGY
Authors: Taketo Ezaki, Kohki Kisima, Shunsuke Shibao, Takuya Matsunaga, Eriel Sandika Pareira, Yohei Kitamura, Kento Takahara, Takashi Iwama, Oltea Sampetrean, Kouhei Ohnishi, Tomoyuki Shimono, Hikaru Sasaki
Journal: Neuro-Oncology (2023)

Abstract Stiffness of human cancers strongly correlate with their pathology, and it is reported that stiffness can be used as a biomarker. Furthermore, comprehensive analysis has suggested the usefulness of cancer stiffness in diagnosis and malignancy prediction and its association with molecular expression, as well as its potential for predicting and diagnosing postoperative complications. Neurosurgeons perform tumor resection relying on the sensations that they feel with their own fingertips (tactile sensation), but it takes years of surgical experience to accurately distinguish brain tumor from the surrounding normal brain tissue. Haptics is a new technology regarding touching sensation. Especially, our technology, real haptics, can communicate, record, and reproduce the real sensation. It is also possible to measure and analyze the physical property such as stiffness of the touching object from the obtained haptic data. We developed a surgical forceps equipped with haptics technology to distinguish brain tumor tissue from surrounding normal brain tissue. three glioblastoma cell lines (SF126, U87, U251) and a malignant meningioma cell line (IOMM-Lee) were each transplanted intracranially into 5 nude mice. Tumor size was periodically monitored and mice were euthanized at appropriate time points. The stiffness of the tumor and normal brain tissue was measured using a master-slave integrated surgical forceps prototype. The results statistically showed that all four types of brain tumor tissues were stiffer than normal brain tissues. (p = 0.001) In addition, malignant meningioma was statistically stiffer than glioblastomas. (p = 0.025) This result is consistent with actual surgical sensations. We have shown that our surgical forceps has the ability to distinguish pathology of brain tumors as well as to distinguish brain tumor from normal brain tissue. The forceps is also helpful for the neurosurgeons to sense minute change in tissue stiffness.
EXTH-62. COMBINATIONAL TREATMENT OF G-QUADRUPLEX STABILIZER CX-5461 AND IONIZING RADIATION POTENTIATES SELECTIVE LETHALITY IN PRECLINICAL ATRX-DEFICIENT GLIOMA MODELS
Authors: Sharvari Dharmaiah, Prit Benny Malgulwar, William E Johnson, Brandon A Chen, Ahsan S Farooqi, Jason Huse
Journal: Neuro-Oncology (2023)

Abstract Mutations in α-thalassaemia/mental retardation X-linked (ATRX) are a critical molecular marker for fatal high-grade glioma (HGG). Standard of care has remained stagnant in the last 30 years, with no therapies approved specifically for ATRX-deficient glioma. ATRX mutations give rise to abnormal DNA secondary G-quadruplex (G4) structures at GC-rich regions of the genome, altering genome-wide accessibility of chromatin and enhancing DNA damage. We aim to use G4 stabilizers, a class of novel small molecule compounds that selectively bind to and stabilize G4s, to enhance DNA damage and induce cell death in ATRX-deficient glioma. Using patient-derived glioma stem cells (GSCs) and the G4 stabilizing compound CX-5461 (Senhwa Biosciences), we evaluated the efficacy of G4 stabilization as a single agent and in combination with ionizing radiation (IR). As IR is standard of care and DNA-damaging, it may hold strong potential to synergize with CX-5461. Here, we report that ATRX-deficient GSCs demonstrate dose-sensitive lethality to CX-5461, compared to controls. Mechanistic studies reveal that CX-5461 activates p53-independent apoptosis, exhibits G2/M arrest in ATRX-deficient GSCs, and upregulates G4s (BG4), replication stress (ATR, RPA32) and DNA damage (ATM, γH2AX) pathways specifically in ATRX-deficient GSCs. These functional findings are corroborated by ATRX-deficient and -intact GSC flank xenograft mouse models, which were separated into the following treatment groups: 1) vehicle, 2) CX-5461 alone, 3) IR alone, 4) CX-5461 and IR (n = 20/group). Excitingly, we demonstrate that combinational treatment leads to profound tumor growth delay exclusively in ATRX-deficient flank tumors compared to vehicle (p = 0.0004), CX-5461 alone (p = 0.0001), or IR alone (p = 0.0002) groups. Multiplex immunohistochemistry of CX-5461 alone and the combinational treatment tumors shows enhanced induction of G4s, replication stress, and DNA damage, recapitulating in vitro findings. Taken together, our work defines mechanisms of action and efficacy for a novel therapeutic strategy for pre-clinical ATRX-deficient HGG, with strong implications for clinical translation.
EPCO-26. INTRATUMORAL HETEROGENEITY OF GBM IDENTIFIED AND CHARACTERIZED BY A MULTISAMPLING APPROACH AND METHYLATION PROFILING
Authors: Omkar Singh, Zied Abdullaev, Yuji Matsumoto, Steven Brem, Donald M O'Rourke, Christos Davatzikos, Kenneth Aldape, MacLean P Nasrallah
Journal: Neuro-Oncology (2023)

Abstract Intratumoral heterogeneity in glioblastoma is known and is considered a key feature of GBM’s clinical aggressiveness. To more fully characterize this phenomenon, we conducted methylation profiling on the EPIC array for 79 regions from 20 glioblastomas. Using the Heidelberg classifier, each of the 20 tumors had at least 1 region with a match to a GBM subtype with &amp;gt;0.84 score. Among these, 6 tumors (30%) showed homogeneous-high score matches to the same GBM subclass, while the remaining 14 tumors (70%) showed heterogeneity in GBM subclass, with either lower scores, or disparate matches to different glioma subtypes. Comparing these subclass-homogeneous versus subclass-heterogeneous groups of tumors using methylCIBERSORT deconvolution, the subclass-heterogeneous cases showed a significantly higher proportions of CD8+ T cells and microglia, and significantly lower proportions of CD4+ T cells, B cells and monocytes. While low tumor purity can be a cause of lower confidence scores in the methylation classifier, we did not find that the subclass-heterogeneous tumors had lower tumor purity compared to subclass-homogeneous cases, suggesting that this heterogeneity was due to factors other than tumor purity. Within the subclass-heterogeneous tumors we identified the common intratumorally most variable probes and examined their characteristics. Compared to the overall distribution of probes on the array, these intratumoral-variable probes were significantly more likely to be intergenic and located on enhancers. Conversely, they were significantly less likely to be on gene promoters and CpG islands. Gene ontology analysis showed that genes associated with these probes were enriched for pathways involved in DNA repair. Overall, our multisampling methylation profiling analysis identifies specific biologic correlates of intratumoral heterogeneity that is not simply due to tumor purity. Methylation changes associated with intratumoral heterogeneity converge on specific genomic patterns that warrant further study.
NIMG-14. AUTOPSY-BASED RADIO-PATHOMIC MAPS REVEAL DEMOGRAPHIC FACTORS IMPACT THE PRESENCE OF TUMOR OUTSIDE CONTRAST ENHANCEMENT IN GLIOMA PATIENTS
Authors: Samuel Bobholz, Allison Lowman, Savannah Duenweg, Aleksandra Winiarz, Margaret Stebbins, Michael Flatley, Biprojit Nath, Fitzgerald Kyereme, Jennifer Connelly, Dylan Coss, Max Krucoff, Anjishnu Banerjee, Peter LaViolette
Journal: Neuro-Oncology (2023)

Abstract Gliomas are vastly heterogenous tumors with wide-ranging pathological signatures; as such, there is a pressing need to understand how individualized factors affect tumor growth patterns to develop treatment plans and improve prognosis. This study used autopsy-based radio-pathomic maps of tumor probability to test the hypothesis that differences in patient sex and age impact the presence of non-enhancing tumor. This study used pre-surgical imaging and demographic data from 501 glioma patients from the UCSF-PDGM dataset. Specifically, T1, T1C, FLAIR, and ADC images were used to generate maps of tumor probability using a previously validated model. This model used autopsy tissue aligned to imaging as ground truth to develop models sensitive to identifying areas of non-enhancing tumor outside of traditional imaging signatures. Thresholded maps were used to delineate areas of tumor presence, and the non-enhancing tumor volume was computed for each patient as the predicted high probability tumor volume within non-enhancing FLAIR hyperintensity. A general linear model was then fit to assess the effect of age and sex on non-enhancing tumor volumes, using tumor grade and contrast-enhancing volume as covariates. Male patients trended towards greater non-enhancing tumor volumes compared to female patients (B=5676.6, p=0.053). Older patients were also found to have less non-enhancing tumor volume compared to younger patients (B=-261.1, p=0.015). These results suggest that demographic characteristics influence the progression of tumor beyond the angiogenic tumor mass and may therefore influence treatment efficacy and prognoses. Future research is essential to understanding how these sex differences relate to the worse prognosis historically observed for males with glioma, and how the reduced presence of non-enhancing tumor in older patients relates to a reduction in plasticity-induced tumor propagation.
CTNI-12. GENOMIC ANALYSIS OF HUMAN BRAIN METASTASES TREATED WITH STEREOTACTIC RADIOSURGERY UNDER THE PHASE-II CLINICAL TRIAL (NCT03398694) REVEALS DNA DAMAGE REPAIR AT THE PERIPHERAL TUMOR EDGE
Authors: Jack Shireman, Quinn White, Namita Agrawal, Zijan Ni, Grace Chen, Chitrasen Mohanty, Lei Zhao, Xiaohu Wang, Atique Ahmed, James Miller, Charles Kulwin, Aaron Cohen-Gadol, Troy Payner, Chih-Ta Lin, Jesse Savage, Brandon Lane, Kevin Shiue, Aaron Kamer, Mitesh Shah, Gopal Iyer, Gordon Watson, Yong Zang, LaKesha Boyd, Tim Lautenschlaeger, Christian Kendziorski, Mahua Dey
Journal: Neuro-Oncology (2023)

Abstract Stereotactic Radiosurgery (SRS) is one of the leading treatment modalities for oligo brain metastasis (BM), however no comprehensive genomic data assessing the effect of radiation on BM in humans exist. Leveraging a unique opportunity, as part of the clinical trial (NCT03398694), we collected post-SRS, delivered via Gamma-knife or LINAC, tumor samples from core and peripheral-edges of the resected tumor to characterize the genomic effects of overall SRS as well as the SRS delivery modality. Using these rare patient samples, we show that SRS results in significant genomic changes at DNA and RNA levels throughout the tumor. Mutations and expression profiles of peripheral tumor samples indicated interaction with surrounding brain tissue as well as elevated DNA damage repair. Central samples show GSEA enrichment for cellular apoptosis while peripheral samples carried an increase in tumor suppressor mutations. There are also significant differences in the transcriptomic profile at the periphery between Gamma-knife vs LINAC.
EXTH-12. CYTOCHROME <i>C</i> OXIDASE SUBUNIT 4 ISOFORM 1 MEDIATES ONCOLYTIC HERPES SIMPLEX VIRUS-1 EFFICACY IN HIGH-GRADE GLIOMA
Authors: Sam Gary, Vincent Laufer, Kaysaw Tuy, Kyung-Don Kang, Claudia Oliva, Corinne Griguer, Anita Hjelmeland, Gregory Friedman
Journal: Neuro-Oncology (2023)

Abstract RATIONALE Outcomes for patients with high-grade glioma (HGG) are dismal despite standard of care surgical resection, radiation, and temozolomide (TMZ) chemotherapy. RESULTS from our Phase I trial of pediatric patients with recurrent HGG suggest oncolytic herpes simplex virus-1 (oHSV) is safe with promising efficacy. However, optimization of oHSV therapy is needed to achieve more durable responses. Based on our prior work with matched pair HGG cell lines and patient-derived xenografts (PDXs) with and without acquired TMZ resistance, oHSV efficacy is enhanced in TMZ-resistant cells with no difference in oHSV entry receptor (CD111) expression. Microarray transcriptomic data of four PDXs with and without TMZ resistance revealed downregulation of interferon (IFN) responses. Cytochrome c oxidase subunit 4 isoform 1 (COX4I1) is expressed in recurrent HGG samples and cell lines. While COX4I1 positively regulates influenza virus replication, no study has investigated the role of COX4I1 in mediating oncolytic virotherapy efficacy. HYPOTHESIS We hypothesized that COX4I1 expression mediates HGG sensitivity to oHSV through suppression of IFN signaling. METHODS Using previously published models, oHSV cytotoxicity was assessed in vitro using Alamar Blue and CellTiter-Glo assays. oHSV infectivity and CD111 protein expression was assessed by flow cytometry. COX4I1 protein expression was measured by immunoblot. mRNA expression of IFN-stimulated genes was assessed by qPCR. RESULTS COX4I1 overexpression increased oHSV cytotoxicity and infectivity compared to empty vector controls. Short hairpin RNA knockdown of COX4I1 decreased oHSV cytotoxicity and infectivity in TMZ-resistant cells compared to pLKO controls. IFN-stimulated genes IFNB1, TMEM173, DDX58, IFIH1, and OAS1 were all significantly decreased in COX4I1 overexpressing cells and TMZ-resistant cells compared to parental lines. CONCLUSIONS Overexpression of COX4I1 sensitizes HGG cells to oHSV, and COX4I1 knockdown de-sensitizes TMZ-resistant HGG cells to oHSV, suggesting a novel role of COX4I1 in mediating HGG sensitivity to oHSV.
CTNI-16. USE OF PREDICTIVE SCORE-BASED HISTORICAL CONTROL DATA IN SINGLE-ARM TRIALS
Authors: Wonsuk Yoo, William Kennedy, Amy Hong, Nader Sanai
Journal: Neuro-Oncology (2023)

Abstract Even though the randomized controlled trials (RCTs) are still the preferred approach to evaluate the effects of treatments, single-arm study designs have been traditionally used in Phase II oncology clinical trials. The single-arm studies using historical control or external control might be inevitable and even fatal when concurrent controls are impractical or unethical in rare and high-risk diseases. Due to recruiting difficulty, ethical and economic reasons, the single-arm trials can be a good option to test the experimental efficacy with the external control data of historical control rates for early efficacy phase 2 trials in glioblastoma. The FDA guidelines on external control data focus on the use of patient-level data from other clinical trials or real-world data (RWD), and so there is no guidance for summary-level historical control. Furthermore, there exist methodological issues to use historical data like identification of relevant data, amount of discounting (time difference and dissimilarity), prior robustness or operating characteristics. In this study, we propose a synthetic data based predictive scoring method optimally to match the historical control data with the characteristic conditions of the experimental studies. We consider both a binary (PFS on six months) and survival (median PFS) endpoints as surrogates for Phase 2 single-arm trials in newly diagnosed and recurrent glioblastoma patients. We perform meta-analysis to summarize the endpoints and the related socio-demographic, treatment and genetic factors from the summary-level historical data. Then we generate the synthetic patients based on the meta-summarized data. The generalized boosted regression models will be used to identify significant characteristics affecting the survival of GBM patients using the synthetic data. Finally the predictive score-based historical data model will be developed to provide the optimal matching with the characteristics of the experimental studies. This study will be validated using existing patient-level data as well as cross-validation methods.
SURG-31. DEFINING THE NEW POSSIBILITIES FOR CESIUM BRACHYTHERAPY IN PATIENTS WITH PERIVENTRICULAR GBM
Authors: Faina Ablyazova, Anurag Sharma, Lyu Huang, Lin Wang, Netanel Ben-Shalom, Jason Ellis, Randy D'Amico, John Boockvar, Louis Potters, A Gabriella Wernicke
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Re-irradiation of patients with external beam radiotherapy (EBRT) for recurrent glioblastoma (GBM) continues to present a therapeutic dilemma due to a high risk of radiation induced necrosis (RN). In contrast, brachytherapy represents a safer, more conformal radiation option aimed at optimizing local control while minimizing the risk of brain tissue damage. Immediate intra-operative implantation with brachytherapy prevents tumor repopulation and offers patients two procedures in one setting. However, due to the risk of seed migration, surgical resection and brachytherapy in periventricular regions was deemed unachievable. In heavily pretreated periventricular GBM, where further EBRT is complicated by RN, a barrier between the ventricular lining and tumor cavity is needed to prevent seed migration. We present two patients where such a barrier allowed successful implantation of brachytherapy to improve disease control. METHODS Two patients, previously treated with surgery and EBRT, presented with recurrent GBM abutting the ventricles. Following GTR of the tumors, a barrier was created by patching the ventricle with Gelfoam to prevent seed migration. Intraoperative brachytherapy implantation of suture stranded Cs-131 seeds (Isoray) for patient 1 and collagen embedded Cs-131 (GammaTile) for patient 2 was performed. A total of 20 Cs-131 seeds on strings threaded through Surgicel, and 6 GammaTiles (24 Cs-131 seeds), were used implanted in patients 1 and 2, respectively. Surgicel covered the implanted seeds and the resection cavity filled with Adherus. RESULTS Post-operative CT scan demonstrated all 20 Cs-131 seeds and 24 Cs-131 seeds in the surgical cavities of patients 1 and 2, respectively, and had serial post operative imaging with MRI scans showing Cs-131 seeds layering surgical cavity, as late as 6 months in total follow up. To date, both patients have had durable local control and no seed migration.
EXTH-51. IDENTIFYING REGULATORS OF HETEROGENEITY IN DMGS USING SCREGCLUST
Authors: Irem Yildirim, Ida Larsson, Sven Nelander
Journal: Neuro-Oncology (2023)

Abstract Diffuse Midline Gliomas (DMGs) are pediatric brain tumors that arise in the pons, thalamus or the brainstem. DMGs present a pressing clinical problem since they cannot be surgically removed and respond poorly to radio- and chemotherapies. Like adult gliomas, DMGs present a high degree of intra-tumoral heterogeneity, with cells adopting different levels of differentiation similar to oligodendrocytes, astrocytes, precursor and mesenchymal cells. These different phenotypes possibly play distinct roles in tumor progression. Yet, we lack a good understanding of the underlying mechanisms of DMG heterogeneity. Here, we present a novel strategy to uncover regulator genes of DMG heterogeneity in a comprehensive and unbiased fashion, using an integration of machine learning with Cas9-based Perturb-seq. We first use a new data-driven modeling technique, termed single cell regulatory-driven clustering (scRegClust; Larsson et al., BioRxiv 2023) to uncover transcriptional modules, and their upstream transcriptional and kinase regulators. The goal of this analysis is to identify regulator genes that control cellular processes relevant to the disease, thereby enhancing our understanding of DMGs and uncover potential therapeutic targets. Applied to recently available single-cell data from 90 DMG patients, scRegClust revealed 160 regulators of meta-modules including oligodendrocyte-like, oligodendrocyte-progenitor-like, astrocyte-like and mesenchymal like cells. To validate the importance of these regulators, we are establishing a Perturb-seq experimental pipeline by combining pooled CRISPR knock-out and single cell RNA sequencing in patient-derived DMG cell lines. By perturbing the candidate regulators both in vitro and in vivo we aim to evaluate their impact on DMG tumorigenicity. This comprehensive strategy will ultimately increase our understanding of the molecular processes in DMGs and present the functional significance of these regulators and their involvement in disease progression.
QOL-02. MONITORING GBM PATIENT HEALTH-RELATED QUALITY OF LIFE AND QUALITY ADJUSTED LIFE MONTHS DURING INDIVIDUALIZED MULTIMODAL IMMUNOTHERAPY USING EQ-5D-5L
Authors: Peter Van de Vliet, Jennifer Makalowski, Linde Kampers, Tobias Sprenger, Volker Schirrmacher, Wilfried Stuecker, Stefaan Van Gool
Journal: Neuro-Oncology (2023)

Abstract DC vaccination emerges as effective treatment for patients with GBM. Besides overall survival, Health-Related Quality of Life (HRQoL) during and after treatment is an important qualitative assessment. We explored the usability of the self-reporting EQ-5D-5L instrument (), available in 14 languages, to determine the Health Utility Index (HUI) and calculate Quality Adjusted Life Months (QALM) in GBM patients during individualized multimodal immunotherapy (IMI). Selection criteria for this retrospective analysis were the start of IMI between 15 October 2021 and May 2023, and availability of at least 5 HRQoL measurements with EQ-5D-5L. Nineteen GBM patients (9 females, 10 males) met these criteria. Median age at diagnosis was 52 years (range 21-67). Median Karnofsky performance index was 80 (60-100). The HUI at time of first diagnosis was unknown. The median HUI at start of immunotherapy was 0.868 (1-0.346). Fifteen patients received IMI as part of first-line treatment. Four patients were treated at time of relapse. Patients received in median 2 IO-Vac® vaccines (0-3) and 6 immunogenic cell death immunotherapy courses (4-12). Sixteen patients were still alive in median 11 months (6-48) after first diagnosis. Three patients died respectively 11, 16, 34 months after diagnosis. The patient response rate to the EQ-5D-5L instrument was high. A median of 7 HRQoL measurements were registered per patient (5-15). One patient did not appropriately answer the EQ-5D-5L questionnaire due to active refusal. The median life time between start of IMI and last time point for measurement of HRQoL was 12.5 months (7.8-47.5). The Quality Adjusted life time between each time point was calculated based on the HUI for each patient. The life time reduction was -0.9 months (-4.2-0), resulting in a median QALM of 12 months (6.3-45.9). EQ-5D-5L can be used to determine the QALMs as qualitative basis for cost-effectiveness calculations for innovative treatments like IMI.